Author + information
- Weijing Feng1,2,
- Wanbing He1,2,
- Yinyin Zhang1,2,
- Mongheng Wang5,
- Jingfeng Wang1,2,
- Kun Zhang1,2,
- Yu Liu3,
- Jie Chen1,2,
- Qingqing Cai4 and
- Hui Huang1,2
- 1Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- 2Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China
- 3Department of Cardiology, the People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- 4Department of Medical Oncology, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- 5Department of Physiology, Augusta University, Augusta, GA, USA
The accumulation of advanced oxidation protein products (AOPPs) is an established risk factor for cardiovascular events. Cardiomyocyte apoptosis has been implicated as a crucial process in cardiac remodeling during chronic kidney disease (CKD). However, whether AOPPs affect cardiomyocyte apoptosis and subsequent cardiac remodeling in CKD is still unclear. Thus, we aim to test the effects of AOPPs on cardiomyocyte apoptosis in CKD.
Rats were randomly divided into sham-operated group (n=10) and 5/6 nephrectomy (STNx) group (n=10). Characteristics in sham-operated rats and STNx rats were collected. The concentrations of serum AOPPs were determined by a multi-mode microplate reader with a 96 well microplate at different time courses. In vitro, cardiomyocytes were exposed to AOPPs (100 ug/ml) for various times. Expression of the related proteins was analyzed using Western blot. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was used to detect apoptotic cells.
Serum concentrations of AOPPs in CKD rats increased in a time-dependent manner but no significant change in sham-operated rats over time. Compared with sham-operated rats, CKD rats showed a significant increase in serum AOPPs levels at the 6th week (42.32±4.12μmol/L vs. 66.49±6.20μmol/L, P<0.05), 9th week (41.67±3.65μmol/L vs. 88.12±7.36μmol/L, P<0.05) and 13th week (40.48±3.08μmol/L vs. 104.70±7.66μmol/L, P<0.05) after surgery, respectively. Additionally, the cardiomyocyte apoptosis, as indicating by TUNEL-staining, in CKD rats was nearly 3-fold higher than sham-operated rats at the 13th week after surgery by TUNEL-staining (1.36 ± 0.04% vs. 0.28±0.03%, P<0.05). Interestingly, the correlation analysis revealed that serum levels of AOPPs were positively correlated with apoptosis rates of cardiomyocyte in CKD rats (R2= 0.76, P<0.01). In vitro, AOPPs exacerbated cardiomyocyte apoptosis and up-regulated pro-apoptotic Bax and caspase-3 expression via activating JNK and endoplasmic reticulum stress. These effects were reversed by nicotinamide adenine dinucleotide phosphate oxidase inhibition.
These results demonstrate for the first time that AOPPs exacerbates cardiomyocyte apoptosis via activating JNK and endoplasmic reticulum stress, which suggests that targeting AOPPs may be a strategy for improving cardiac remodeling in CKD.